Benign prostatic hyperplasia is benign adenoma generated in a transitional zone of the prostate that wraps the urethra. Patients with benign prostatic hyperplasia complain of bladder outlet obstructive symptoms or bladder irritative symptoms. Examples of bladder outlet obstructive symptoms include a hesitation before urine flow starts, straining, a weak urinary stream, an intermittent urinary stream, dribbling at the end of urination, prolongation of urination and overflow incontinence. Examples of bladder irritative symptoms include urinary frequency at daytime, urinary frequency at night, urinary urgency, a feeling of incomplete emptying and a reduced voided volume per micturition. Functional obstruction and mechanical obstruction are involved in the development of these urinary disturbances due to benign prostatic hyperplasia. Further, these functional and mechanical obstructions cause secondary changes in detrusor muscle or nerves, which induce the complicated pathological phenomena such as bladder irritative symptoms and bladder outlet obstructive symptoms.
At present, for examples, α1-receptor blockers, anti-androgen agents, plant preparations, amino acid preparations, or the like are used as a therapeutic agent for benign prostatic hyperplasia. Among these, examples of the α1-receptor blockers include tamsulosin hydrochloride, prazosin hydrochloride, terazosin hydrochloride and urapidil. Examples of the anti-androgen agents include chlormadinone acetate, allylestrenol, gestonorone caproate, oxendolone and finasteride. The α1-receptor blockers inhibit the functional urethral obstruction, that is, contractions of prostatic smooth muscle induced by noradrenaline, secreted by stimulation of the sympathetic nerve, via the α1-receptor. The anti-androgen agents inhibit the mechanical obstruction, that is, a rise in urethral resistance resulting from the pressure caused by the enlarged prostate itself. However, although the α1-receptor blockers and anti-androgen agents are recognized to be effective for bladder outlet obstructive symptoms of benign prostatic hyperplasia, their effects on improvement of bladder irritative symptoms are insufficient. The plant preparations and amino acid preparations, which have anti-inflammatory activity, anti-edema activity, or the like, improve the bladder irritative symptoms by alleviating the outflow obstruction at the bladder neck; but their effects are weak and the dose required is large so that they are a burden to aged people. Under these circumstances, there exists a need for a therapeutic agent to alleviate bladder irritative symptoms.
Tricyclic compounds having the activity to prolong the intervals of bladder contractions and pharmaceutically acceptable salts thereof are known as therapeutic agents for urinary incontinence (WO97/14672 and WO98/46587). However, it is not known that the compound groups have the activity to remit bladder irritative symptoms associated with benign prostatic hyperplasia.